The second near-infrared (NIR-Ⅱ, 1000-1700 nm) fluorescence imaging (FLI) can overcome the problems of strong tissue absorption, high scattering, and auto-fluorescence, significantly improve the spatiotemporal resolution, signal-to-noise ratio, and penetration depth, so as to play a vital role in the diagnosis and treatment of major diseases. Among NIR-Ⅱ fluorescent materials, small organic molecules present great potential for clinical transform by their good biocompatibility, fast metabolism, and high biosafety. At present, most always-on type NIR-Ⅱ small molecules lack accuracy in the detection of lesions, leading to uncertainty in diagnosis. Activatable NIR-Ⅱ small molecules can generate specific fluorescent signals under the activation of biomarkers, which greatly improves the accuracy and reliability of detection. This review systematically summarizes the recent progresses on activatable NIR-Ⅱ small molecules for bioimaging, focusing on their molecular design strategies and bioimaging performance. In addition, the current problems, challenges, and future development directions are discussed.